DESCRIPTION: The long-term goal of this research project is to understand the complex regulatory mechanism of ERK2, a MAP kinase. MAP kinases are important elements of signal transduction pathways initiated by hormones, cytokines, or environmental stress. MAP kinases such as ERK2 are activated after phosphorylation by MAP/ERK kinases (MEKs), which are themselves activated by Ras/Raf proteins following cell stimulation. As such, these enzymes may present useful therapeutic targets. MAP kinases have several interesting properties, including a complex dual phosphorylation regulatory mechanism and a high substrate specificity for hydroxyamino acids that are followed by proline in the target protein's sequence. Few protein kinase systems have been thoroughly investigated and none has crystallographic data for both the inactive and active or phosphorylated forms of the same enzyme.